Methods and compositions for deterring abuse of opioid containing dosage forms

ABSTRACT

This invention relates to an abuse deterrent dosage form of opioid analgesics, wherein an analgesically effective amount of opioid analgesic is combined with a polymer to form a matrix.

FIELD OF INVENTION

This invention pertains to abuse deterrent compositions containing adrug (e.g., an analgesic opioid). Additionally, the invention relates toa method of administering a dose of an analgesic from a dosage form,which is abuse deterrent.

BACKGROUND OF THE INVENTION

The class of drugs exhibiting opium or morphine-like properties arereferred to as opioids, or opioid agonists. Certain opioids act asagonists, interacting with stereo specific and saturable binding sitesin the brain and other tissues. Endogenous opioid-like peptides arepresent in areas of the central nervous system that are presumed to berelated to the perception of pain; to movement, mood and behavior, andto the regulation of neuroendocrinological functions. Three classicalopioid receptor types, mu (μ), delta (δ), and kappa (κ), have beenstudied extensively. Each of these receptors has a unique anatomicaldistribution in the brain, spinal cord, and the periphery. Most of theclinically used opioids are relatively selective for μ receptors,reflecting their similarity to morphine. However, it is important tonote that opioid containing drugs that are relatively selective atstandard doses will often interact with additional receptor subtypeswhen given at sufficiently high doses, leading to possible changes intheir pharmacological effect. This is especially true as opioid dosesare escalated to overcome tolerance.

The potential for the development of tolerance, physical and/orpsychological, dependence (i.e., addiction) with repeated opioid use isa characteristic feature of most opioid containing drugs. Thepossibility of developing addiction is one of the major concerns in theuse of opioids for the management of pain. Another major concernassociated with the use of opioids is the diversion of these drugs froma patient in legitimate pain to other individuals (non-patients) forrecreational purposes.

Drug abusers and/or addicts typically may take a dosage form containingone or more opioid analgesics and crush, shear, grind, chew, dissolveand/or heat, extract or otherwise damage the product so that asignificant amount or even an entire amount of the drug becomesavailable for immediate absorption by 1) injection, 2) inhalation,and/or 3) oral consumption.

There are three basic patterns of behavior leading to opioid abuse. Thefirst involves individuals whose opioid drug use begins in the contextof medical treatment and who obtain their initial drug supplies throughprescriptions from physicians. The second begins with experimental or“recreational” drug use and progresses to more intensive use. A thirdpattern of abuse involves users who begin in one or another of thepreceding ways but later switch to oral opioids such as methadone,obtained from organized addiction treatment programs.

There are various routes of administration an abuser may commonlyattempt to abuse an opioid containing drug formulation. The most commonmethods include 1) parenteral (e.g. intravenous injection), 2)intranasal (e.g., snorting), and 3) repeated oral ingestion of excessivequantities of orally administered tablets or capsules. One mode of abuseof oral solid drugs involves the extraction of the opioid component fromthe dosage form by first mixing the dosage form with a suitable solvent(e.g., water), and then subsequently extracting the opioid componentfrom the mixture for use in a solution suitable for intravenousinjection of the opioid to achieve a “high.”

Attempts have been made to diminish abuse of orally administered opioiddrugs. These attempts generally centered on the inclusion in the oraldosage form of an opioid antagonist which is not orally active but whichwill substantially block the analgesic effects of the opioid if oneattempts to dissolve the opioid and administer it parenterally.

For example, commercially available Talwin®Nx tablets fromSanofi-Winthrop contain a combination of pentazocine and naloxone.Pentazocine is a partial agonist of μ receptors and also has affinityfor κ receptors, whereas, naloxone is an antagonist of μ receptors.Talwin®Nx contains pentazocine hydrochloride equivalent to 50 mg baseand naloxone hydrochloride equivalent to 0.5 mg base. Talwin®Nx isindicated for the relief of moderate to severe pain. The amount ofnaloxone present in this combination has no action when taken orally,and will not interfere with the pharmacologic action of pentazocine.However, this amount of naloxone given by injection has profoundantagonistic action to opioid analgesics. Thus, the inclusion ofnaloxone is intended to curb a form of misuse of oral pentazocine, whichoccurs when the dosage form is solubilized and injected. Therefore, thisdosage has lower potential for parenteral misuse than previous oralpentazocine formulations.

U.S. Pat. No. 6,559,159 (Carroll et al.) describes the use of kappareceptors antagonist for the treatment of opioid related addictions. Onesuch compound is naltrexone, which is commercially available in thetablet form Revia® for the treatment of alcohol dependence and for theblockade of exogenously administered opioids. (Physicians Desk Reference57^(th) ed., Montvale, N.J.)

U.S. Pat. No. 6,375,957 (Kaiko et al.) describes in detail thecombination of opioid agonist, NSAID, and an orally active opioidantagonist. The purpose of adding the opioid antagonist is the same asdiscussed above.

U.S. Pat. No. 4,457,933 (Gordon et al.) describes in detail a method fordecreasing both the oral and parenteral abuse potential of analgesicagents such as oxycodone, propoxyphene and pentazocine by combining ananalgesic dose of the analgesic agents with naloxone in specific,relatively narrow ranges.

U.S. Pat. No. 6,228,863 B1 (Palermo et al.) describes a method forreducing the abuse potential of an oral dosage form of an opioidanalgesic, whereby an orally active opioid agonist is combined with anopioid antagonist into an oral dosage form requiring at least a two-stepextraction process to be separated from the opioid agonist, the amountof opioid antagonist included being sufficient to counteract opioideffects if extracted together with the opioid agonist and administeredparenterally.

The prior art describes several other methods and compositions tominimize the abuse of an opioid containing drug. One such method isdiscussed in U.S. Pat. No. 6,593,367 (Dewey et al.), describing a methodwhereby the addiction-related behavior of a mammal suffering fromaddiction could be changed by a combination of drugs. The methodincludes administering to the mammal an effective amount of gamma vinylGABA (GVG) or a pharmaceutically acceptable salt, or an enantiomer or aracemic mixture, where the effective amount is sufficient to diminish,inhibit or eliminate behavior associated with craving or use of thecombination of abused drugs.

U.S. Pat. Nos. 4,175,119 and 4,459,278 (Porter et al.) describecompositions and methods useful for the prevention of accidental and/orintentional oral overdoses of a drug.

In summary, various attempts have been made and are described in priorart to develop abuse-deterrent dosage forms. Clearly there is a need fora delivery system for commonly used oral dosage formulations (e.g.,immediate release, sustained or extended release and delayed release) ofdrugs, and in particular analgesics such as opioid analgesics, forpatients seeking drug therapy and which deters abuse and minimizes orreduces the potential for physical or psychological dependency.

SUMMARY OF THE INVENTION

The present invention includes a therapeutic pharmaceutical compositionincluding an analgesic, a gel forming polymer, a surfactant present insufficient amount to cause nasal irritation, and an inert excipient insufficient amount to cause emesis if greater than a prescribed amount ofthe analgesic included in the therapeutic composition is ingested. Thepresent invention also includes a therapeutic pharmaceutical compositionincluding an analgesic, a gel forming polymer, a surfactant present insufficient amount to cause nasal irritation, and an emetic in sufficientamount to cause emesis if greater than a prescribed amount of theanalgesic included in the therapeutic composition is ingested.

In one embodiment, the therapeutic pharmaceutical composition can beformed into a unit dose including an opioid analgesic, a gel formingpolymer, a nasal tissue irritating amount of a surfactant, and an emeticin sufficient amount to cause emesis if greater than a prescribed amountof the analgesic included in the therapeutic composition is ingested. Inone embodiment, the polymer includes one or more of polyethylene oxide(e.g., having average molecular weight ranging form about 300,000 toabout 5,000,000), polyvinyl alcohol (e.g., having a molecular weight ofabout 20,000 to 200,000), hydroxypropyl methyl cellulose (e.g., having amolecular weight of about 10,000 to 1,500,000), and a carbomer (e.g.,having a molecular weight ranging of about 700,000 to 4,000,000,000),the nasal irritant includes about 1 to 5 percent by weight sodium laurylsulfate, and the emetic includes less than about 0.6 to 2.0 gm of zincsulfate.

The present invention also provides methods of making a pharmaceuticalcomposition suitable for deterring drug abuse including one or moresteps of providing an analgesic, a gel forming polymer having a suitableviscosity, a nasal tissue irritant and emetic, controlling the molecularweight or viscosity of the gel forming polymer, controlling the amountof nasal tissue irritant such that nasal tissue irritation occurs ifinhaled, controlling the amount of emetic such that emesis ensues onlyif more than a prescribed amount of the analgesic is consumed, andcombining the analgesic, gel forming polymer, nasal tissue irritant andemetic to form a therapeutic composition.

The present invention includes a therapeutic pharmaceutical compositionincluding an analgesic, a gel forming polymer, a surfactant present insufficient amount to cause mucosal tissue irritation, and an emetic insufficient amount to cause emesis if greater than a prescribed amount ofthe analgesic included in the therapeutic composition is ingested.

Compositions and methods of the present invention can deter abuse of theanalgesic by forming a viscous gel upon contact with a solvent such thatthe gel and analgesic cannot be easily drawn into a syringe and/or byinducing nasal irritation if the composition is inhaled, and/or byinducing emesis if more than a prescribed dosage amount of the analgesicis consumed.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be better understood by examining thefollowing figures which illustrate certain properties of the presentinvention wherein:

FIG. 1 shows a percentage amount of certain opioid drugs available insolution for injection after standard dosage forms are crushed andexposed to a solvent;

FIG. 2 shows a percentage amount of certain opioid drugs available insolution for injection after dosage forms of the present invention arecrushed and exposed to a solvent;

FIG. 3 shows an amount of drug recoverable from a solvent contacted withfive embodiments of the present invention compared to a standardformulation;

FIG. 4 shows a dissolution profile of six embodiments of the presentinvention;

FIG. 5 a shows various methods used to formulate the dosage forms havingone or more abuse deterrent properties of the present invention;

FIG. 5 b shows a particular dosage form having one or more abusedeterrent properties of the present invention;

FIG. 5 c shows a particular dosage form having one or more abusedeterrent properties of the present invention and a disintegrant;

FIG. 6 shows a process flow chart for the manufacture of a dosage formof the present invention; and

FIG. 7 shows a dissolution profile of three extended releaseformulations of the present invention.

With reference to the Figures, features that are the same across theFigures are denoted with the same reference numbers.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes an abuse deterrent formulation forreducing the potential for one or more of a) parenteral abuse, b)inhalation (e.g., intranasal abuse), and/or c) oral abuse of a drug,typically an opioid analgesic type drug, for satisfaction of a physicalor psychological dependence. In one embodiment, the present inventiondeters parenteral abuse by providing a pharmaceutical composition whichincludes an analgesic with one or more gel forming agents such that uponcontact with a solvent (e.g., water), the agents swell by absorbing thesolvent thereby 1) entrapping the drug in a gel matrix and/or 2)reducing or preventing a significant amount of the opioid analgesic frombeing drawn into a syringe. In one embodiment, the present inventiondeters inhalation abuse by providing a pharmaceutical composition whichincludes a therapeutically active pharmaceutical (e.g., an analgesic),with one or more mucous membrane, mucosa or mucosal tissue irritants(collectively referred to as mucous membrane irritants). In oneembodiment, the mucosal tissue is nasal passageway tissue.

Upon contact with a mucous membrane, the irritants induce temporary painand/or irritation of the membranes and/or tissues to thereby deterabuse. For example, if inhaled by snorting, the mucous membrane in thenasal passageway will be irritated and result in pain to the individual.In one embodiment, the present invention provides a pharmaceuticalcomposition which includes an analgesic with one or more emetics, suchthat after oral consumption of more than a typically prescribed amountof the dosage form, emesis is induced.

In one embodiment, two or more of the abuse deterrents can be combinedinto one composition according to the present invention.

The present invention describes formulations which have abuse deterrentproperties as described herein. Examples of specific oral solid dosageforms containing morphine, hydrocodone and oxycodone were evaluatedusing suitable analytical test methods, such as UV/VISspectrophotometry. In the evaluation, dosage forms were crushed andcontacted with a small amount of water (about a teaspoon or tablespoon).After attempting to dissolve the dosage form, the resultant material wasdrawn into a syringe, volume was measured and opioid content wasquantitated. As shown in FIG. 1, almost 100% of the opioid can beextracted from standard formulations. Comparatively, as shown in FIG. 2,an abuse deterrent formulation of the present invention for the sameopioids, provides a significantly lower percentage of extractableopioid. As shown in FIG. 1, approximately 93%, 103% and 99% of theopioid analgesic drugs contained in a dosage form were recoverable usingthe above described techniques. Comparatively, as shown in FIG. 2, usingan abuse deterrent polymer of the present invention, only 9%, 5%, and 6%of the opioid analgesic drugs were recoverable.

In another embodiment, the present invention is a pharmaceuticalcomposition that includes an opioid analgesic, one or more gel formingagents, and one or more mucous membrane irritants or nasal passagewaytissue irritants. In another embodiment, the present invention includesa pharmaceutical composition, which includes an analgesic, one or moregel forming agents and one or more emetics as described herein. Inanother embodiment, the present invention includes a pharmaceuticalcomposition, which includes an opioid analgesic, one or more mucousmembrane irritants or nasal passageway tissue irritants and one or moreemetics as described herein. In one particular embodiment, the presentinvention includes a pharmaceutical composition which includes ananalgesic, one or more gel forming agents, one or more mucous membraneirritants and/or nasal passageway tissue irritants, and one or moreemetics.

Each of the components of the pharmaceutical composition of the presentinvention are described in more detail below.

A. Drugs Suitable for Use With the Present Invention

Any drug, therapeutically acceptable drug salt, drug derivative, druganalog, drug homologue, or polymorph can be used in the presentinvention. In one embodiment, the drug can be orally administered. Incertain embodiments, drugs susceptible to abuse are used. Drugs commonlysusceptible to abuse include psychoactive drugs and analgesics,including but not limited to opioids and drugs that can causepsychological and/or physical dependence on the drug.

A drug for use in the present invention can be one or more of thefollowing: alfentanil, amphetamines, buprenorphine, butorphanol,carfentanil, codeine, dezocine, diacetylmorphine, dihydrocodeine,dihydromorphine, diphenoxylate, diprenorphine, etorphine, fentanyl,hydrocodone, hydromorphone, β-hydroxy-3-methylfentanyl,levo-α-acetylmethadol, levorphanol, lofentanil, meperidine, methadone,methylphenidate, morphine, nalbuphine, nalmefene, o-methylnaltrexone,naloxone, naltrexone, oxycodone, oxymorphone, pentazocine, pethidine,propoxyphene, remifentanil, sufentanil, tilidine and tramodol, salts,derivatives, analogs, homologues, polymorphs thereof, and mixtures ofany of the foregoing.

In one embodiment, a pharmaceutical composition of the present inventionincludes one or more opioids such as hydrocodone, morphine and oxycodoneand/or salts thereof, as the therapeutically active ingredient.Typically when processed into a suitable dosage form, as described inmore detail below, the drug can be present in such dosage forms in anamount normally prescribed, typically about 0.5 to about 25 percent on adry weight basis, based on the total weight of the formulation.

With respect to analgesics in unit dose form, such an amount can betypically from about 5, 25, 50, 75, 100, 125, 150, 175 or 200 mg. Moretypically, the drug can be present in an amount from 5 to 500 mg or even5 to 200 mg. In other embodiments, a dosage form contains an appropriateamount of drug to provide a therapeutic effect.

B. Gel Forming Agents

As described above, the present invention can include one or more gelforming agents. The total amount of gel forming agent is typically about3 to about 40 percent on a dry weight basis of the composition.

Suitable gel forming agents include compounds that, upon contact with asolvent (e.g., water), absorb the solvent and swell, thereby forming aviscous or semi-viscous substance that significantly reduces and/orminimizes the amount of free solvent which can contain an amount ofsolublized drug, and which can be drawn into a syringe. The gel can alsoreduce the overall amount of drug extractable with the solvent byentrapping the drug in a gel matrix. In one embodiment, typical gelforming agents include pharmaceutically acceptable polymers, typicallyhydrophilic polymers, such as hydrogels.

In some embodiments, the polymers exhibit a high degree of viscosityupon contact with a suitable solvent. The high viscosity can enhance theformation of highly viscous gels when attempts are made by an abuser tocrush and dissolve the contents of a dosage form in an aqueous vehicleand inject it intravenously.

More specifically, in certain embodiments the polymeric material in thepresent invention provides viscosity to the dosage form when it istampered. In such embodiments, when an abuser crushes and dissolves thedosage form in a solvent (e.g., water or saline), a viscous orsemi-viscous gel is formed. The increase in the viscosity of thesolution discourages the abuser from injecting the gel intravenously orintramuscularly by preventing the abuser from transferring sufficientamounts of the solution to a syringe to cause a desired “high” onceinjected.

Suitable polymers include one or more pharmaceutically acceptablepolymers selected from any pharmaceutical polymer that will undergo anincrease in viscosity upon contact with a solvent. Preferred polymersinclude polyethylene oxide, polyvinyl alcohol, hydroxypropyl methylcellulose and carbomers. In preferred embodiments, the polymers include:

a) Polyethylene Oxide

-   -   In some embodiments, the polymer includes polyethylene oxide.        The polyethylene oxide can have an average molecular weight        ranging from about 300,000 to about 5,000,000, more preferably        from about 600,000 to about 5,000,000, and most preferably at        least about 5,000,000. In one embodiment, the polyethylene oxide        includes a high molecular weight polyethylene oxide.    -   In one embodiment, the average particle size of the polyethylene        oxide ranges from about 840 to about 2,000 microns. In another        embodiment, the density of the polyethylene oxide can range from        about 1.15 to about 1.26 g/ml. In another embodiment, the        viscosity can range from about 8,800 to about 17,600 cps.    -   The polyethylene oxide used in a directly compressible        formulation of the present invention is preferably a homopolymer        having repeating oxyethylene groups, i.e., —(—O—CH₂-CH₂—)_(n)—,        where n can range from about 2,000 to about 180,000. Preferably,        the polyethylene oxide is a commercially available and        pharmaceutically acceptable homopolymer having moisture content        of no greater than about 1% by weight. Examples of suitable,        commercially available polyethylene oxide polymers include        Polyox®, WSRN-1105 and/or WSR-coagulant, available from Dow        chemicals.    -   In some embodiments, the polyethylene oxide powdered polymers        can contribute to a consistent particle size in a directly        compressible formulation and eliminate the problems of lack of        content uniformity and possible segregation.        b) Polyvinyl Alcohol    -   In one embodiment, the gel forming agent includes polyvinyl        alcohol. The polyvinyl alcohol can have a molecular weight        ranging from about 20,000 to about 200,000. The specific gravity        of the polyvinyl alcohol can range from about 1.19 to about 1.31        and the viscosity from about 4 to about 65 cps. The polyvinyl        alcohol used in the formulation is preferably a water-soluble        synthetic polymer represented by —(—C₂H₄O—)_(n)—, where n can        range from about 500 to about 5,000. Examples of suitable,        commercially available polyvinyl alcohol polymers include PVA,        USP, available from Spectrum Chemical Manufacturing Corporation,        New Brunswick, N.J. 08901.        c) Hydroxypropyl Methyl Cellulose    -   In one embodiment, the gel forming agent includes hydroxypropyl        methyl cellulose (Hypromellose). The hydroxypropyl methyl        cellulose can have a molecular weight ranging from about 10,000        to about 1,500,000, and typically from about 5000 to about        10,000, i.e., a low molecular weight hydroxypropyl methyl        cellulose polymer. The specific gravity of the hydroxypropyl        methyl cellulose can range from about 1.19 to about 1.31, with        an average specific gravity of about 1.26 and a viscosity of        about 3600 to 5600. The hydroxypropyl methylcellulose used in        the formulation can be a water-soluble synthetic polymer.        Examples of suitable, commercially available hydroxypropyl        methylcellulose polymers include Methocel K100 LV and Methocel        K4M, available from Dow chemicals.        d) Carbomers    -   In one embodiment, the present invention includes carbomers. The        carbomers can have a molecular weight ranging from 700,000 to        about 4,000,000,000. The viscosity of the polymer can range from        about 4000 to about 39,400 cps. Examples of suitable,        commercially available carbomers include carbopol 934P NF,        carbopol 974P NF and carbopol 971P NF, available from Noveon        Pharmaceuticals.

Following the teachings set forth herein, other suitable gel formingagents can include one or more of the following polymers:ethylcellulose, cellulose acetate, cellulose acetate propionate,cellulose acetate butyrate, cellulose acetate phthalate and cellulosetriacetate, cellulose ether, cellulose ester, cellulose ester ether, andcellulose, acrylic resins comprising copolymers synthesized from acrylicand methacrylic acid esters, the acrylic polymer may be selected fromthe group consisting of acrylic acid and methacrylic acid copolymers,methyl methacrylate copolymers, ethoxyetlryl methacrylates, cyanoetlrylmethacrylate, poly(acrylic acid), poly(methaerylic acid), methacrylicacid alkylamide copolymer, poly(methyl methacrylate), polymethacrylate,poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkylmethacrylate copolymer, poly(methacrylic acid anhydride), and glycidylmethacrylate copolymers.

Any of the above described polymers can be combined together or combinedwith other suitable polymers, and such combinations are within the scopeof the present invention.

In one embodiment, the abuse deterrent, gel forming agent can preventless than or equal to about 95%, 94%, 70%, 60%, 54%, 50%, 45%, 40%, 36%,32%, 30%, 27%, 20%, 10%, 9%, 6%, 5% or 2% of the total amount of drug ina dosage form from being recovered from a solvent in contact with adosage form of the present invention. As shown in FIG. 3, formulationsA3, B3, C3, D3 and E3 reduce the amount of drug extractable orrecoverable from a dosage for of the present invention. Specifically,formulation A3 provides for recovery of 26.77% of the total amount ofdrug in the dosage form, formulation B3 provides for recovery of 31.8%of the total amount of drug in the dosage form, formulation C3 providesfor recovery of 35.75% of the total amount of drug in the dosage form,formulation D3 provides for recovery of 35.8% of the total amount ofdrug in the dosage form, and formulation E3 provides for recovery of42.5% of the total amount of drug in the dosage form. In FIG. 3, allfive formulations A3 through E3 are compared with a standard dosage formof oxycontin, which provided for recovery of 98.6% of the total amountof drug in the dosage form.

The five formulations A3 through E3 are set forth in Examples 14 through18, respectively.

It should be noted that the above described formulations also havedissolution profiles as determined by the USP 2-paddle method, as shownin FIG. 4. In particular, for formulations A3 through E3, about 50% toabout 82% of each formulation dissolves after about 15 minutes and about80% to about 95% dissolves after 90 minutes. FIG. 4 further includes thedissolution profile of Formulation F3. With respect to FIG. 4, thecomposition of formulation F3 is set forth in Example 19.

The above described gel forming agents can be further optimized asnecessary or desired in terms of viscosity, molecular weight, etc.

C. Mucous Membrane Irritants and/or Nasal Passageway Tissue Irritants

As described above, the present invention can include one or more mucousmembrane irritants and/or nasal passageway tissue irritants. In oneembodiment, suitable mucous membrane irritants and/or nasal passagewaytissue irritants include compounds that are generally consideredpharmaceutically inert, yet can induce irritation. Such compoundsinclude, but are not limited to surfactants. In one embodiment, suitablesurfactants include sodium lauryl sulfate, poloxamer, sorbitanmonoesters and glyceryl monooleates. Other suitable compounds arebelieved to be within the knowledge of a practitioner skilled in therelevant art, and can be found in the Handbook of PharmaceuticalExcipients, 4th Ed. (2003), the entire content of which is herebyincorporated by reference.

In one embodiment of the present invention, the irritant can be presentin amount of from 1 to 10 percent by weight on a solid basis, preferably1 to 5 percent by weight on a solid basis. In another embodiment, theamount of irritant can be present in an amount from 1 to 3 percent byweight.

In certain embodiments, the irritant can deter abuse of a dosage formwhen a potential abuser tampers with a dosage form of the presentinvention. Specifically, in such embodiments, when an abuser crushes thedosage form, the irritant is exposed. The irritant discouragesinhalation of the crushed dosage form by inducing pain and/or irritationof the abuser's mucous membrane and/or nasal passageway tissue. In oneembodiment, the irritant discourages inhalation (e.g., via snortingthrough the nose) by inducing pain and/or irritation of the abuser'snasal passageway tissue.

In one embodiment, the present invention includes one or more mucousmembrane irritants to cause irritation of mucous membranes locatedanywhere on or in the body, including membranes of the mouth, eyes andintestinal tract. Such compositions can deter abuse via oral,intra-ocular or rectal or vaginal routes.

The above-described irritants can be further optimized as necessary ordesired in terms of concentration, irritation severity, etc.

D. Emetics

As described above, the present invention can include one or moreemetics or emesis inducing agents. Preferably, the emetic is apharmaceutically acceptable inert excipient that only induces emesisafter a certain threshold amount is ingested. In another embodiment, theemetic can be a pharmaceutically active emetic.

In one embodiment, the amount of emetic present in a pharmaceuticalcomposition of the present invention can be tied directly to the amountof drug in the pharmaceutical composition. Thus, by controlling thequantity of the emetic compound in the pharmaceutical composition,emesis can be avoided if normal prescription directions are followed.However, if an overdosage occurs by ingesting more than a prescribedquantity of a drug in a pharmaceutical composition of the presentinvention, the amount of ingested emetic can exceed the threshold amountnecessary to induce emesis.

In some embodiments, the threshold amount of emetic for inducing emesiscan be reached when the normal prescription directions areinappropriately increased by factors of 2, 3, 4, 5, 6, 7, or 8 times, ormore. Thus, in some embodiments, the amount of emetic present in apharmaceutical composition of the present invention is an amount suchthat the amount of emetic ingested does not exceed the threshold amountnecessary for inducing emesis until a subject ingests 2, 3, 4, 5, 6, 7,or 8 or more times the amount of drug normally prescribed. In someembodiments, emesis can preclude death or serious illness in thesubject.

In one embodiment, the emetic includes zinc sulfate. Zinc sulfate is anexcipient, which can induce emesis when more than about 0.6 to 2.0 gm isingested, typically more than about 0.6 gm, or about 5 to 25 percent byweight on a solid basis, more typically about 5 to 10 percent by weight.Accordingly, pharmaceutical compositions of the present invention can beeasily designed to induce emesis if a prescribed dosage is exceededand/or if prescription directions are not followed for dosage formscontaining a composition of the present invention. Typically, suitableembodiments of the present invention include less than about 0.6 to 2.0gm of zinc sulfate.

For example, in one embodiment, if a practitioner desires to create adosage form that will induce emesis only after four or more dosage formsare ingested, the amount of zinc sulfate in each dosage form should notexceed about 0.19 gm. Thus, if three dosage forms are ingested, theamount of emetic is 0.57 gm, which is less than a typical thresholdamount of the particular emetic. However, if a fourth dosage form having0.19 gm. of zinc sulfate is ingested, the amount of emetic exceeds thethreshold amount, and emesis is induced.

The above-described emetics can be further optimized as necessary ordesired in terms of concentration in the pharmaceutical composition,etc.

Other suitable emetics can include one or more of cephaeline, methylcephaeline, psychotrine, O-methylpsychotrine and emetamine.

E. Other Ingredients

The present invention can also optionally include other ingredients toenhance dosage form manufacture from a pharmaceutical composition of thepresent invention and/or alter the release profile of a dosage formingincluding a pharmaceutical composition of the present invention.

Some embodiments of the present invention include one or morepharmaceutically acceptable fillers/diluents. In one embodiment, AvicelPH (Microcrystalline cellulose) is a filler used in the formulation. TheAvicel PH can have an average particle size ranging from 20 to about 200μm, preferably about 100 μm. The density ranges from 1.512–1.668 g/cm³.The Avicel PH should have molecular weight of about 36,000. Avicel PHeffectiveness is optimal when it is present in an amount of from about10 to 65 percent, by weight on a solid basis, of the formulation.Typical fillers can be present in amounts from 10 to 65 percent byweight on a dry weight basis. Other ingredients can include sugarsand/or polyols.

Other ingredients can also include dibasic calcium phosphate having aparticle size of about 75 to about 425 microns and a density of about0.5 to about 1.5 g/ml, as well as calcium sulfate having a particle sizeof about 1 to about 200 microns and a density of about 0.6 to about 1.3g/ml and mixtures thereof. Further, lactose having a particle size ofabout 20 to about 400 microns and a density of about 0.3 to about 0.9g/ml can also be included.

In some embodiments of the invention, the fillers which can be presentat about 10 to 65 percent by weight on a dry weight basis, also functionas binders in that they not only impart cohesive properties to thematerial within the formulation, but can also increase the bulk weightof a directly compressible formulation (as described below) to achievean acceptable formulation weight for direct compression. In someembodiments, additional fillers need not provide the same level ofcohesive properties as the binders selected, but can be capable ofcontributing to formulation homogeneity and resist segregation from theformulation once blended. Further, preferred fillers do not have adetrimental effect on the flowability of the composition or dissolutionprofile of the formed tablets.

In one embodiment, the present invention can include one or morepharmaceutically acceptable disintegrants. Such disintegrants are knownto a skilled artisan. In the present invention, disintegrants caninclude, but are not limited to, sodium starch glycolate (Explotab®)having a particle size of about 104 microns and a density of about 0.756g/ml, starch (e.g., Starch 21) having a particle size of about 2 toabout 32 microns and a density of about 0.462 g/ml, Crospovidone® havinga particle size of about 400 microns and a density of about 1.22 g/ml,and croscarmellose sodium (Ac-Di-Sol) having a particle size of about 37to about 73.7 microns and a density of about 0.529 g/ml. Thedisintegrant selected should contribute to the compressibility,flowability and homogeneity of the formulation. Further the disintegrantcan minimize segregation and provide an immediate release profile to theformulation. In some embodiments, the disintegrant (s) are present in anamount from about 2 to about 25 percent by weight on a solid basis ofthe directly compressible formulation.

In one embodiment, the present invention can include one or morepharmaceutically acceptable glidants, including but not limited tocolloidal silicon dioxide. In one embodiment, colloidal silicon dioxide(Cab-O-Sil®) having a density of about 0.029 to about 0.040 g/ml can beused to improve the flow characteristics of the formulation. Suchglidants can be provided in an amount of from about 0.1 to about 1percent by weight of the formulation on a solid basis. It will beunderstood, based on this invention, however, that while colloidalsilicon dioxide is one particular glidant, other glidants having similarproperties which are known or to be developed could be used providedthey are compatible with other excipients and the active ingredient inthe formulation and which do not significantly affect the flowability,homogeneity and compressibility of the formulation.

In one embodiment, the present invention can include one or morepharmaceutically acceptable lubricants, including but not limited tomagnesium stearate. In one embodiment, the magnesium stearate has aparticle size of about 450 to about 550 microns and a density of about1.00 to about 1.80 g/ml. In one embodiment, magnesium stearate cancontribute to reducing friction between a die wall and a pharmaceuticalcomposition of the present invention during compression and can ease theejection of the tablets, thereby facilitating processing. In someembodiments, the lubricant resists adhesion to punches and dies and/oraid in the flow of the powder in a hopper and/or into a die. In anembodiment of the present invention, magnesium stearate having aparticle size of from about 5 to about 50 microns and a density of fromabout 0.1 to about 1.1 g/ml is used in a pharmaceutical composition. Incertain embodiments, a lubricant should make up from about 0.1 to about2 percent by weight of the formulation on a solids basis. Suitablelubricants are stable and do not polymerize within the formulation oncecombined. Other lubricants known in the art or to be developed whichexhibit acceptable or comparable properties include stearic acid,hydrogenated oils, sodium stearyl fumarate, polyethylene glycols, andLubritab®.

In certain embodiments, the most important criteria for selection of theexcipients are that the excipients should achieve good contentuniformity and release the active ingredient as desired. The excipients,by having excellent binding properties, and homogeneity, as well as goodcompressibility, cohesiveness and flowability in blended form, minimizesegregation of powders in the hopper during direct compression.

In another embodiment, the present invention can include an opioidantagonist in addition to the other ingredients, or as a substitute forone of the other abuse deterrent ingredients of a formulation of thepresent invention. Suitable antagonists are described above. Oneparticular antagonist includes naloxone. As described above, typicallynaloxone has no action when taken orally, and will not interfere withthe pharmacologic action of an opioid agonist. However, when given byinjection naloxone can have profound antagonistic action to opioidagonists. An appropriate antagonist can be used in combination with oneor more of gel forming agents, mucous membrane irritants and/or nasalpassageway tissue irritants, or emetics in the present invention. Anappropriate antagonist can also be used as a substitute for one or moreof gel forming agents, mucous membrane irritants and/or nasal passagewaytissue irritants, or emetics in the present invention. Suitable opioidreceptor antagonists can include but are not limited to the antagonistsdescribed in U.S. Pat. Nos. 6,559,159 and 6,375,957, the entire contentof which are hereby incorporated by reference.

F. Dosage Forms of the Present Invention

A pharmaceutical composition of the present invention including one ormore drug components, one or more of gel forming agents, mucous membraneirritants and/or nasal passageway tissue irritants, and emetics, andoptionally other ingredients, can be suitably modified and processed toform a dosage form of the present invention. As referred to herein andin FIGS. 5 a, 5 b, 5 c and 6, an “abuse deterrent composition” or “ADC”(labeled “40” in these Figures) includes a composition having one ormore gel forming agents and/or mucous membrane irritants and/or nasalpassageway tissue irritants, and/or emetics according to the teachingsset for-th herein. In this manner, an abuse deterrent composition can belayered onto, coated onto, applied to, admixed with, formed into amatrix with, and/or blended with a drug and optionally otheringredients, thereby providing a therapeutic composition of the presentinvention.

As shown in FIG. 5 a, an abuse deterrent composition can be combinedwith a drug and/or opioid analgesic (e.g., hydrocodone) in one or morelayered dosage forms. According to the present invention, drug 50 can bea layer on or near the surface (I) of ADC 40 of the present invention,or sandwiched between two or more distinct layers (II and III) of ADC 40of the present invention. In other embodiments, drug 50 can be a coating(IV) on ADC 40. Drug 50 can be any of the pharmaceutically activeingredients (e.g., opioids) described herein and can be combined withother excipients, e.g. disintegrants including but not limited to sodiumstarch glycolate or Explotab®.

As shown in FIG. 5 b an abuse deterrent composition 40 of the presentinvention can be combined with drug 50, e.g., hydrocodone, in a blendedmixture. In such embodiments, drug 50 and ADC 40 can be evenly mixed.

As shown in FIG. 5 c abuse deterrent composition 40 of the presentinvention can be combined with drug 50, e.g., hydrocodone, in a blendedmixture with other ingredients 60, e.g., a disintegrant.

FIG. 6 shows one embodiment of the present invention for making a dosageform of the present invention. Specifically, a first step (step 1) ofFIG. 4 shows drug 50 combined with abuse deterrent composition 40 of thepresent invention. ADC 40 can contain one or more gel forming agentsand/or mucous membrane irritants and/or nasal passageway tissueirritants, and/or emetics according to the teachings set forth herein.In a second step (step 2), the combination of drug 50 and ADC 40 canthen be blended with other ingredients 60, e.g. disintegrants andlubricants, to form a mix 100. Lastly, in a third step (step 3)combination 100 can then be processed using conventional practices 110,e.g., compression, into a suitable unit dosage form 120, e.g. tablets.

Suitable formulations and dosage forms of the present invention includebut are not limited to powders, caplets, pills, suppositories, gels,soft gelatin capsules, capsules and compressed tablets manufactured froma pharmaceutical composition of the present invention. The dosage formscan be any shape, including regular or irregular shape depending uponthe needs of the artisan.

Compressed tablets including the pharmaceutical compositions of thepresent invention can be direct compression tablets or non-directcompression tablets. In one embodiment, a dosage form of the presentinvention can be made by wet granulation, and dry granulation (e.g.,slugging or roller compaction). The method of preparation and type ofexcipients are selected to give the tablet formulation desired physicalcharacteristics that allow for the rapid compression of the tablets.After compression, the tablets must have a number of additionalattributes such as appearance, hardness, disintegrating ability, and anacceptable dissolution profile.

Choice of fillers and other excipients typically depend on the chemicaland physical properties of the drug, behavior of the mixture duringprocessing, and the properties of the final tablets. Adjustment of suchparameters is understood to be within the general understanding of oneskilled in the relevant art. Suitable fillers and excipients aredescribed in more detail above.

The manufacture of a dosage form of the present invention can involvedirect compression and wet and dry granulation methods, includingslugging and roller compaction. However, in the present invention, it ispreferred to use direct compression techniques because of the lowerprocessing time and cost advantages.

Accordingly, and as described further below, a directly compressiblepharmaceutical composition of the present invention can be designedfollowing the teachings set forth herein that can deter one or more ofa) parenteral abuse of a drug, b) inhalation abuse of a drug, and c)oral abuse of a drug.

Such compositions and dosage forms are formed according to the presentinvention are described. Steps for making the compositions or dosageforms include the step of providing one or more drugs and/or analgesicsdescribed above and an amount of a gel forming polymer having a desiredmolecular weight or viscosity as described above, and/or providing anasal tissue irritant, and/or providing an emetic in the amounts asdescribed above.

By controlling the molecular weight and/or viscosity of the gel formingpolymer, and/or by controlling the amount of mucous membrane irritantand/or nasal tissue irritant such that nasal tissue irritation occurs ifthe composition is inhaled (e.g. snorting), and/or by controlling theamount of emetic such that emesis ensues if more than a prescribedamount of the analgesic is consumed, a therapeutic composition suitablefor use to deter drug abuse can be formed. The compositions according tothe present invention can deter abuse of the analgesic by (1) forming aviscous substance upon contact with a solvent such that the substanceand analgesic cannot be easily drawn into a syringe and/or (2) byinducing mucous membrane irritation and/or nasal tissue irritation ifthe composition is inhaled, and/or (3) by inducing emesis if more than aprescribed amount of the analgesic is consumed.

The present invention can be used to manufacture immediate release, andcontrolled drug release formulations. Controlled release formulationscan include delayed release and extended release oral solid dosagepreparations. Examples 25 (formulation A7 of FIG. 7), 26 (formulation B7of FIG. 7) and 27 (formulation C7 of FIG. 7) provide embodiments of theinvention that can provide controlled release of a drug. The releaseprofiles of the controlled release dosage forms of the present inventionare shown in FIG. 7. The dosage forms in FIG. 7 include hydrocodonebitartrate (HCBT) as an active. As shown in FIG. 7, about 80 to 95% ofthe drug in a controlled release dosage form of the present invention isreleased after about 10 hours, as compared to an immediate releasedosage form (a conventional dosage form) which is at least 75% dissolvedafter about 45 minutes. Other opioid formulations having an extendedeffect, which can be modified to further include one or more of theabuse deterrent compositions of the present invention, are described inU.S. Pat. No. 6,572,885, the entire content of which is herebyincorporated by reference.

Certain aspects of the present invention may be better understood asillustrated by the following examples, which are meant by way ofillustration and not limitation.

EXAMPLE 1

A direct compression formulation, as shown in Table 1, for an immediaterelease opioid analgesic, e.g. hydrocodone bitartrate, tablet having 5mg of hydrocodone bitartrate was formed by weighing each componentseparately and mixing the hydrocodone bitartrate and the polymer in aV-blender for about 5 to 10 minutes at low shear conditions or in a highshear blender by mixing 2 to 5 minutes. The other formulation excipientswere added to the above blend excepting the lubricant and mixed at thesame rate for additional 5 to about 10 minutes. Finally, the lubricant,magnesium stearate was added to the formulation and blended at the samerate for an additional 3 to 5 minutes. This polymeric matrix containingthe drug and other excipients was further compressed on a rotary tabletpress to form pharmaceutically acceptable tablets.

The tablets were monitored for weight, hardness, thickness andfriability. The tablets were tested for assay, release characteristics(in-vitro dissolution method) and abuse deterrent properties.

Samples of the tablets were subjected to dissolution testing using USPApparatus 2 (U.S. Pharmacopoeia, XXVI, 2003), speed 50 rpm at 37° C., inpurified water as dissolution medium for a period of 90 minutes. Theacceptable dissolution criterion is not less than 75 percent of the drugdissolved in 45 minutes.

To evaluate abuse deterrent properties of the formulation a method hasbeen developed that mimics the street abuser's method for abuse.

-   (i) The tablets are crushed and the resulting powder is placed into    table/teaspoon.-   (ii) Measured amount of water is added to the spoon. Contents of the    spoon are heated for about 1 to 2 minutes.-   (iii) Contents of the spoon are withdrawn using a syringe equipped    with a needle.-   (iv) The volume of the sample removed from the spoon is measured and    the contents of the syringe are tested for the active, using a    suitable analytical test method such as UV/VIS spectrophotometry.

TABLE 1 Component Weight (mg)/tablet Hydrocodone bitartrate 5 Polyvinylalcohol 160 Avicel PH 102 333 Starch 21 54 Zinc sulfate 30 Explotab 15Cab-O-Sil 1.5 Magnesium stearate 1.5 Total 600

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method detailed above was about 34percent.

EXAMPLE 2

TABLE 2 Component Weight (mg)/tablet Hydrocodone bitartrate 5 Polyvinylalcohol 160 Crospovidone 90 Avicel PH 102 120 Starch 21 43 Zinc sulfate30 Cab-O-Sil 1 Magnesium stearate 1 Total 450

As shown by Table 2, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 5 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 31 percent.

EXAMPLE 3

TABLE 3 Component Weight (mg)/tablet Hydrocodone bitartrate 5 Polyox 70Crospovidone 152 Avicel PH 102 304 Zinc sulfate 150 Sodium laurylsulfate 1 Cab-O-Sil 14 Magnesium stearate 4 Total 700

As shown by Table 3, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 5 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 11 percent.

EXAMPLE 4

TABLE 4 Component Weight (mg)/tablet Hydrocodone bitartrate 5 Polyvinylalcohol 80 Polyox 15 Avicel PH 102 300 Zinc sulfate 50 Sodium laurylsulfate 7 Crospovidone 100 Cab-O-Sil 2 Magnesium stearate 1 Total 560

As shown by Table 4, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 5 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 6.5 percent.

EXAMPLE 5

TABLE 5 Component Weight (mg)/tablet Hydrocodone bitartrate 5 MethocelK100 LV 25 Avicel PH 102 300 Zinc sulfate 50 Sodium lauryl sulfate 7Crospovidone 100 Cab-O-Sil 2 Magnesium stearate 1 Total 490

As shown by Table 5, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 5 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 17 percent.

EXAMPLE 6

TABLE 6 Component Weight (mg)/tablet Oxycodone hydrochloride 5 Polyox 25Avicel PH 102 300 Zinc sulfate 50 Sodium lauryl sulfate 7 Crospovidone100 Cab-O-Sil 2 Magnesium stearate 1 Total 490

As shown by Table 6, a direct compression formulation of oxycodonehydrochloride immediate release formulation including a dosage of 5 mgof oxycodone hydrochloride was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 70% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 9 percent.

EXAMPLE 7

TABLE 7 Component Weight (mg)/tablet Morphine sulfate 20 Polyox 20Avicel PH 102 300 Zinc sulfate 50 Sodium lauryl sulfate 7 Crospovidone100 Cab-O-Sil 2 Magnesium stearate 1 Total 500

As shown by Table 7, a direct compression formulation of morphinesulfate immediate release formulation including a dosage of 20 mg ofmorphine sulfate was prepared and tested using the blending conditionsand procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 16 percent.

EXAMPLE 8

TABLE 8 Component Weight (mg)/tablet Morphine sulfate 20 Polyvinylalcohol 160 Avicel PH 102 318 Zinc sulfate 30 Explotab 30 Starch 21 54Cab-O-Sil 1.5 Magnesium stearate 1.5 Total 615

As shown by Table 8, a direct compression formulation of morphinesulfate immediate release formulation including a dosage of 20 mg ofmorphine sulfate was prepared and tested using the blending conditionsand procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 12 percent.

EXAMPLE 9

TABLE 9 Component Weight (mg)/tablet Morphine sulfate 40 Polyox 15Avicel PH 102 300 Zinc sulfate 50 Sodium lauryl sulfate 7 Crospovidone100 Cab-O-Sil 2 Magnesium stearate 1 Total 515

As shown by Table 9, a direct compression formulation of morphinesulfate immediate release formulation including a dosage of 40 mg ofmorphine sulfate was prepared and tested using the blending conditionsand procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 15 percent.

EXAMPLE 10

TABLE 10 Component Weight (mg)/tablet Morphine sulfate 40 Polyvinylalcohol 200 Avicel PH 102 278 Zinc sulfate 30 Explotab 30 Starch 21 54Cab-O-Sil 1.5 Magnesium stearate 1.5 Total 635

As shown by Table 10, a direct compression formulation of morphinesulfate immediate release formulation including a dosage of 40 mg ofmorphine sulfate was prepared and tested using the blending conditionsand procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 6 percent.

EXAMPLE 11

TABLE 11 Component Weight (mg)/tablet Hydrocodone bitartrate 7.5 Polyox25 Avicel PH 102 297.5 Crospovidone 100 Zinc sulfate 50 Sodium laurylsulfate 7 Cab-O-Sil 2 Magnesium stearate 1 Total 490

As shown by Table 11, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 7.5 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 5 percent.

EXAMPLE 12

TABLE 12 Component Weight (mg)/tablet Hydrocodone bitartrate 10Polyvinyl alcohol 80 Polyox 15 Avicel PH 102 295 Crospovidone 100 Zincsulfate 50 Sodium lauryl sulfate 7 Cab-O-Sil 2 Magnesium stearate 1Total 560

As shown by Table 12, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 10 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 9.5 percent.

EXAMPLE 13

TABLE 13 Component Weight (mg)/tablet Hydrocodone bitartrate 5 Carbopol971P 10 Avicel PH 102 300 Crospovidone 100 Zinc sulfate 50 Sodium laurylsulfate 7 Cab-O-Sil 2 Magnesium stearate 1 Total 490

As shown by Table 13, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 5 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 27 percent.

EXAMPLE 14

TABLE 14 Formulation A3 Component Weight (mg/tablet) HydrocodoneBitartrate 5 Polyvinyl Alcohol 160 Avicel PH 102 318 Zinc Sulfate 30Starch 21 54 Explotab 30 Cab-O-Sil 1.5 Magnesium Stearate 1.5 Total 600

As shown by Table 14, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 5 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution showed about 62% of the drug dissolved in 45minutes.

The drug extracted by the abuse-test method was about 26.77 percent.

EXAMPLE 15

TABLE 15 Formulation B3 Component Weight (mg/tablet) HydrocodoneBitartrate 5 Polyvinyl Alcohol 160 Avicel PH 102 333 Zinc Sulfate 30Explotab 15 Starch 21 54 Cab-O-Sil 1.5 Magnesium Stearate 1.5 Total 600

As shown by Table 15, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 5 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution showed about 72% of the drug dissolved in 45minutes.

The drug extracted by the abuse-test method was about 31.8 percent.

EXAMPLE 16

TABLE 16 Formulation C3 Component Weight (mg/tablet) HydrocodoneBitartrate 5 Polyvinyl Alcohol 160 Avicel PH 102 120 Zinc Sulfate 30Crospovidone (PVP XL) 40 Starch 21 43 Cab-O-Sil 1 Magnesium Stearate 1Total 400

As shown by Table 16, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 5 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution showed about 75% of the drug dissolved in 45minutes.

The drug extracted by the abuse-test method was about 35.75 percent.

EXAMPLE 17

TABLE 17 Formulation D3 Component Weight (mg/tablet) HydrocodoneBitartrate 5 Polyvinyl Alcohol 160 Avicel PH 102 120 Zinc Sulfate 30Crospovidone (PVP XL) 100 Starch 21 33 Cab-O-Sil 1 Magnesium Stearate 1Total 450

As shown by Table 17, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 5 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution showed about 82% of the drug dissolved in 45minutes.

The drug extracted by the abuse-test method was about 35.8 percent.

EXAMPLE 18

TABLE 18 Formulation E3 Component Weight (mg/tablet) HydrocodoneBitartrate 5 Polyvinyl Alcohol 160 Avicel PH 102 333 Zinc Sulfate 30Starch 21 54 Crospovidone (PVP XL) 15 Cab-O-Sil 1.5 Magnesium Stearate1.5 Total 600

As shown by Table 18, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 5 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution showed about 79% of the drug dissolved in 45minutes.

The drug extracted by the abuse-test method was about 42.5 percent.

EXAMPLE 19

TABLE 19 Formulation F3 Component Weight (mg/tablet) HydrocodoneBitartrate 5 Polyvinyl Alcohol 160 Avicel PH 102 119 Zinc Sulfate 30Crospovidone (PVP XL) 100 Starch 21 33 Cab-O-Sil 1 Magnesium Stearate 2Total 450

As shown by Table 19, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 5 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 54 percent.

EXAMPLE 20

TABLE 20 Component Weight (mg/tablet) Hydrocodone Bitartrate 5 PolyvinylAlcohol 95 Avicel PH 102 192 Zinc Sulfate 30 Starch 21 140 Ac-Di-Sol 35Cab-O-Sil 1 Magnesium Stearate 2 Total 500

As shown in Table 20, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 5 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 60 percent.

EXAMPLE 21

TABLE 21 Component Weight (mg/tablet) Oxycodone Hydrochloride 5 AvicelPH 102 119 Zinc Sulfate 30 Crospovidone (PVP XL) 100 Starch 21 33Cab-O-Sil 1 Magnesium Stearate 2 Total 290

As shown by Table 21, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 5 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 94 percent.

EXAMPLE 22

TABLE 22 Component Weight (mg/tablet) Hydrocodone Bitartrate 5 PolyvinylAlcohol 50 Avicel PH 102 192 Zinc Sulfate 30 Starch 21 140 Ac-Di-Sol 35Cab-O-Sil 1 Magnesium Stearate 2 Total 455

As shown in Table 22, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 5 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 70 percent.

EXAMPLE 23

TABLE 23 Component Weight (mg/tablet) Hydrocodone Bitartrate 5 PolyvinylAlcohol 160 Avicel PH 102 318 Zinc Sulfate 30 Explotab 30 Cab-O-Sil 1.5Magnesium Stearate 1.5 Total 600

As shown in Table 23, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 5 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 33 percent.

EXAMPLE 24

TABLE 24 Component Weight (mg/tablet) Hydrocodone Bitartrate 10 AvicelPH 102 318 Zinc Sulfate 50 Crospovidone (PVP XL) 100 Sodium LaurylSulfate 7 Cab-O-Sil 1.5 Magnesium Stearate 1.5 Total 488

As shown in Table 24, a direct compression formulation of hydrocodonebitartrate immediate release formulation including a dosage of 5 mg ofhydrocodone bitartrate was prepared and tested using the blendingconditions and procedure as stated in Example 1.

An in-vitro dissolution criterion of NLT 75% of the drug dissolved in 45minutes was met.

The drug extracted by the abuse-test method was about 85 percent.

EXAMPLE 25

TABLE 25 Formulation A7 Component Weight (mg/tablet) HydrocodoneBitartrate 22 Polyvinyl Alcohol 250 Cab-O-Sil 1.38 Magnesium Stearate2.76 Total 276.14

An in-vitro dissolution showed about 98% dissolution after 10 hours.

EXAMPLE 26

TABLE 26 Formulation B7 Component Weight (mg/tablet) HydrocodoneBitartrate 44 Polyvinyl Alcohol 450 Cab-O-Sil 1.5 Magnesium Stearate 2.0Total 497.5

An in-vitro dissolution showed about 82% dissolution after 10 hours.

EXAMPLE 27

TABLE 27 Formulation C7 Component Weight (mg/tablet) HydrocodoneBitartrate 88 Polyvinyl Alcohol 600 Cab-O-Sil 1.5 Magnesium Stearate 2.0Total 691.5

An in-vitro dissolution showed about 80% dissolution after 10 hours.

It will be appreciated by persons skilled in the art that numerousvariations and/or modifications may be made to the invention shown inthe specific embodiments without departing form the spirit and scope ofthe invention as broadly described. Further, each and every referencecited above is hereby incorporated by reference as if fully set forthherein.

1. A therapeutic pharmaceutical composition comprising a mixtureincluding (a) at least one opioid analgesic selected from the groupconsisting of alfentanil, buprenorphine, butorphanol, carfentanil,codeine, dezocine, diacetylmorphine, dihydrocodeine, dihydromorphine,diprenorphine, etorphine, fentanyl, hydrocodone, hydromorphone,β-hydroxy-3-methylfentanyl, levo-α-acetylmethadol, levorphanol,lofentanil, meperidine, methadone, morphine, nalbuphine, oxycodone,oxymorphone, pentazocine, pethidine, prepoxyphene, remifentanil,sufentanil, tilidine, tramadol and a pharmaceutically acceptable saltthereof; (b) gel forming polyethylene oxide at about 3 to 40% by weight;(c) at least one disintegrant at about 2 to 25% by weight, selected fromthe group consisting of crospovidone, sodium starch glycolate, andcroscarmellose sodium; and (d) a nasal tissue irritant, wherein thecomposition functions such that less than about 50% of the total amountof opioid analgesic in the composition is recovered when about 490 mg.of the composition is contacted with 15 ml of water.
 2. The therapeuticpharmaceutical composition of claim 1, further comprising an emetic. 3.The therapeutic pharmaceutical composition of claim 1, wherein the gelforming polyethylene oxide has an average molecular weight ranging fromabout 300,000 to about 5,000,000.
 4. The therapeutic pharmaceuticalcomposition of claim 1, wherein the pharmaceutical composition is inunit dose form.
 5. The therapeutic pharmaceutical composition of claim1, wherein the pharmaceutical composition is in a suppository, capsule,caplet, pill, gel, soft gelatin capsule, or compressed tablet form. 6.The therapeutic pharmaceutical composition of claim 1, wherein theanalgesic is present in an amount of about 0.5 to about 25 percent byweight.
 7. The therapeutic pharmaceutical composition of claim 1,wherein the analgesic is hydrocodone or a pharmaceutically acceptablesalt thereof.
 8. The therapeutic pharmaceutical composition of claim 1,wherein the analgesic is oxycodone or a pharmaceutically acceptable saltthereof.
 9. The therapeutic pharmaceutical composition of claim 8,wherein the disintegrant is crospovidone.
 10. The therapeuticpharmaceutical composition of claim 1, wherein the analgesic is morphineor a pharmaceutically acceptable salt thereof.
 11. The therapeuticpharmaceutical composition of claim 1, wherein the analgesic is codeineor a pharmaceutically acceptable salt thereof.
 12. The therapeuticpharmaceutical composition of claim 1, wherein the analgesic ishydromorphone or a pharmaceutically acceptable salt thereof.
 13. Thetherapeutic pharmaceutical composition of claim 1, wherein the analgesicis propoxyphene or a pharmaceutically acceptable salt thereof.
 14. Thetherapeutic pharmaceutical composition of claim 1, wherein the analgesicis tramadol or a pharmaceutically acceptable salt thereof.
 15. Thetherapeutic pharmaceutical composition of claim 1, wherein the analgesiccomprises meperidine or a pharmaceutically acceptable salt thereof. 16.The therapeutic pharmaceutical composition of claim 1, wherein theanalgesic is methadone or a pharmaceutically acceptable salt thereof.17. The therapeutic pharmaceutical composition of claim 1, wherein theanalgesic is pentazocine or a pharmaceutically acceptable salt thereof.18. The therapeutic pharmaceutical composition of claim 1, wherein thedisintegrant is crospovidone.
 19. A therapeutic pharmaceuticalcomposition comprising a mixture including (a) at least one opioidanalgesic selected from the group consisting of alfentanil,buprenorphine, butorphanol, carfentanil, codeine, dezocine,diacetylmorphine, dihydrocodeine, dihydromorphine, diprenorphine,etorphine, fentanyl, hydrocodone, hydromorphone,β-hydroxy-3-methylfentanyl, levo-α-acetylmethadol, levorphanol,lofentanil, meperidine, methadone, morphine, nalbuphine, oxycodone,oxymorphone, pentazocine, pethidine, propoxyphene, remifentanil,sufentanil, tilidine, tramadol and a pharmaceutically acceptable salt,thereof; (b) gel forming polyethylene oxide at about 3 to 40% by weight;(c) a surfactant at about 1 to 10% by weight; (d) at least onedisintegrant at about 2 to 25% by weight, wherein the disintegrant isselected from the group consisting of crospovidone, sodium starchglycolate, and croscarmellose sodium; and (e) wherein the compositionfunctions such that less than about 50% of the total amount of opioidanalgesic in the composition is recovered when about 490 mg. of thecomposition is contacted with 15 ml of water.
 20. The therapeuticpharmaceutical composition of claim 19, further comprising an emetic.21. The therapeutic pharmaceutical composition of claim 19, wherein thegel forming polyethylene oxide has an average molecular weight rangingfrom about 300,000 to about 5,000,000.
 22. The therapeuticpharmaceutical composition of claim 19, wherein the pharmaceuticalcomposition is in unit dose form.
 23. The therapeutic pharmaceuticalcomposition of claim 19, wherein the pharmaceutical composition is in asuppository, capsule, caplet, pill, gel, soft gelatin capsule, orcompressed tablet form.
 24. The therapeutic pharmaceutical compositionof claim 19, wherein the analgesic is present in an amount of about 0.5to about 25 percent by weight.
 25. The therapeutic pharmaceuticalcomposition of claim 19, wherein the analgesic is hydrocodone or apharmaceutically acceptable salt thereof.
 26. The therapeuticpharmaceutical composition of claim 19, wherein the analgesic isoxycodone or a pharmaceutically acceptable salt thereof.
 27. Thetherapeutic pharmaceutical composition of claim 26, wherein thedisintegrant is crospovidone.
 28. The therapeutic pharmaceuticalcomposition of claim 19, wherein the analgesic is morphine or apharmaceutically acceptable salt thereof.
 29. The therapeuticpharmaceutical composition of claim 19, wherein the analgesic is codeineor a pharmaceutically acceptable salt thereof.
 30. The therapeuticpharmaceutical composition of claim 19, wherein the analgesic ishydromophone or a pharmaceutically acceptable salt thereof.
 31. Thetherapeutic pharmaceutical composition of claim 19, wherein theanalgesic is propoxyphene or a pharmaceutically acceptable salt thereof.32. The therapeutic pharmaceutical composition of claim 19, wherein theanalgesic is tramadol or a pharmaceutically acceptable salt thereof. 33.The therapeutic pharmaceutical composition of claim 19, wherein theanalgesic is meperidine or a pharmaceutically acceptable salt thereof.34. The therapeutic pharmaceutical composition of claim 19, wherein theanalgesic is methadone or a pharmaceutically acceptable salt thereof.35. The therapeutic pharmaceutical composition of claim 19, wherein theanalgesic is pentazocine or a pharmaceutically acceptable salt thereof.36. The therapeutic pharmaceutical composition of claim 19, wherein thedisintegrant is crospovidone.
 37. A therapeutic pharmaceuticalcomposition comprising: a mixture including (a) at least one opioidanalgesic selected from the group consisting of alfentanil,buprenorphine, butorphanol, carfentanil, codeine, dezocine,diacetylmorphine, dihydrocodeine, dihydromorphine, diprenorphine,etorphine, fentanyl, hydrocodone, hydromorphone,β-hydroxy-3-methylfentanyl, levo-α-acetylmethadol, levorphanol,lofentanil, meperidine, methadone, morphine, nalbuphine, oxycodone,oxymorphone, pentazocine, pethidine, propoxyphene, remifentanil,sufentanil, tilidine, tramadol and a pharmaceutically acceptable saltthereof; (b) gel forming polyethylene oxide at about 3 to about 40percent by weight; (c) at least one disintegrant at about 2 to 25percent by weight wherein the disintegrant is selected from the groupconsisting of crospovidone, sodium starch glycolate, and croscarmellosesodium; and (d) sodium lauryl sulfate at about 1 to 10 percent byweight.
 38. The therapeutic pharmaceutical composition of claim 37,further comprising an emetic.
 39. The therapeutic pharmaceuticalcomposition of claim 37, wherein the gel forming polyethylene oxide hasan average molecular weight ranging from about 300,000 to about5,000,000.
 40. The therapeutic pharmaceutical composition of claim 37,wherein the pharmaceutical composition is in unit dose form.
 41. Thetherapeutic pharmaceutical composition of claim 37, wherein thepharmaceutical composition is in a suppository, capsule, caplet, pill,gel, soft gelatin capsule, or compressed tablet form.
 42. Thetherapeutic pharmaceutical composition of claim 37, wherein theanalgesic is present in an amount of about 0.5 to about 25 percent byweight.
 43. The therapeutic pharmaceutical composition of claim 37,wherein the analgesic is hydrocodone or a pharmaceutically acceptablesalt thereof.
 44. The therapeutic pharmaceutical composition of claim37, wherein the analgesic is oxycodone or a pharmaceutically acceptablesalt thereof.
 45. The therapeutic pharmaceutical composition of claim44, wherein the disintegrant is crospovidone.
 46. The therapeuticpharmaceutical composition of claim 37, wherein the analgesic ismorphine or a pharmaceutically acceptable salt thereof.
 47. Thetherapeutic pharmaceutical composition of claim 37, wherein theanalgesic is codeine or a pharmaceutically acceptable salt thereof. 48.The therapeutic pharmaceutical composition of claim 37, wherein theanalgesic is hydromorphone or a pharmaceutically acceptable saltthereof.
 49. The therapeutic pharmaceutical composition of claim 37,wherein the analgesic is propoxyphene or a pharmaceutically acceptablesalt thereof.
 50. The therapeutic pharmaceutical composition of claim37, wherein the analgesic is tramadol or a pharmaceutically acceptablesalt thereof.
 51. The therapeutic pharmaceutical composition of claim37, wherein the analgesic is meperidine or a pharmaceutically acceptablesalt thereof.
 52. The therapeutic pharmaceutical composition of claim37, wherein the analgesic is methadone or a pharmaceutically acceptablesalt thereof.
 53. The therapeutic pharmaceutical composition of claim37, wherein the analgesic is pentazocine or a pharmaceuticallyacceptable salt thereof.
 54. The therapeutic pharmaceutical compositionof claim 37, wherein the disintegrant is crospovidone.